Hypofractionated Stereotactic Radiotherapy for Non-breast or Prostate Cancer Oligometastases: A Tail of Survival Beyond 10 Years

Purpose and Objective(s): We sought to analyze the long-term follow-up of patients treated with hypofractionated, stereotactic radiotherapy (HSRT) for oligometastases from malignancies other than breast or prostate cancer.Materials and Methods: From 2001 to 2006, 82 cancer patients with 1–5 radiographically apparent metastatic lesions (in 1–3 organs) from primary sites other than breast or prostate cancer, were enrolled on a prospective study of HSRT. Freedom from widespread metastasis (FFWM) was defined from date of enrollment until death, an event (i.e., widespread distant metastasis not amenable to local therapy), or last radiographic study. Local recurrence was scored as an event if pathologically confirmed or if a treated lesion increased by ≥20% using RECIST criteria. Prognostic variables were assessed using Cox regression analysis.Results: The mean age was 61 ± 11 years, with a male to female ratio of 46:36. The most common metastatic sites were liver (50%), lung (48%), thoracic lymph nodes (18%), and bone (5%). Sixty-one patients (74%) had 1 involved organ and 18 (22%) had 1 lesion treated. The preferred dose-fractionation scheduled was 50 Gy in 10 fractions (52 patients). The median follow-up was 1.7 years. Eleven patients lived >5 years, and 6 lived >10 years. The 5-year OS, PFS, FFWM, and LC rates were 13.4, 7.3, 18.3, and 63.4%, and the 10-years OS, PFS, FFWM, and patient LC rates were 7.3, 6.1, 13.4, and 62.2%, respectively. A greater net gross tumor volume (GTV) was significantly adverse for OS (p < 0.01) and LC (p < 0.01). For FFWM, net GTV was not a significant factor (p = 0.14). Four patients remain alive at >13 years from enrollment and treatment, without evidence of active disease.Conclusion: A small subset of select non-breast, non-prostate cancer patients with limited metastasis treated with HSRT are long-term survivors. Net GTV is a significant factor for tumor control and survival. Further research is needed to help better select patients most likely to benefit from local therapy for metastatic disease

Uptake Rate of Cationic Mitochondrial Inhibitor MKT-077 Determines Cellular Oxygen Consumption Change in Carcinoma Cells

<div><h3>Objective</h3><p>Since tumor radiation response is oxygen-dependent, radiosensitivity can be enhanced by increasing tumor oxygenation. Theoretically, inhibiting cellular oxygen consumption is the most efficient way to increase oxygen levels. The cationic, rhodacyanine dye-analog MKT-077 inhibits mitochondrial respiration and could be an effective metabolic inhibitor. However, the relationship between cellular MKT-077 uptake and metabolic inhibition is unknown. We hypothesized that rat and human mammary carcinoma cells would take up MKT-077, causing a decrease in oxygen metabolism related to drug uptake.</p> <h3>Methods</h3><p>R3230Ac rat breast adenocarcinoma cells were exposed to MKT-077. Cellular MKT-077 concentration was quantified using spectroscopy, and oxygen consumption was measured using polarographic electrodes. MKT-077 uptake kinetics were modeled by accounting for uptake due to both the concentration and potential gradients across the plasma and mitochondrial membranes. These kinetic parameters were used to model the relationship between MKT-077 uptake and metabolic inhibition. MKT-077-induced changes in oxygen consumption were also characterized in MDA-MB231 human breast carcinoma cells.</p> <h3>Results</h3><p>Cells took up MKT-077 with a time constant of ∼1 hr, and modeling showed that over 90% of intracellular MKT-077 was bound or sequestered, likely by the mitochondria. The uptake resulted in a rapid decrease in oxygen consumption, with a time constant of ∼30 minutes. Surprisingly the change in oxygen consumption was proportional to uptake rate, not cellular concentration. MKT-077 proved a potent metabolic inhibitor, with dose-dependent decreases of 45–73% (p = 0.003).</p> <h3>Conclusions</h3><p>MKT-077 caused an uptake rate-dependent decrease in cellular metabolism, suggesting potential efficacy for increasing tumor oxygen levels and radiosensitivity <em>in vivo</em>.</p> </div

Phase 2 Comprehensive Acquisition Plan (CAP)- Georgia Department of Transportation: Safe Trips in a Connected Transportation Network ITS4US Deployment Project [Title from Cover]

693JJ32250011The Georgia Department of Transportation ITS4US Deployment project, Safe Trips in a Connected Transportation Network (ST-CTN), is leveraging innovative solutions, existing deployments, and collaboration to make a positive impact using transportation technology to support safety, mobility, sustainability, and accessibility. The ST-CTN concept is comprised of an integrated set of advanced transportation technology solutions (connected vehicle, transit signal priority, machine learning, predictive analytics) to support safe and complete trips, with a focus on accessibility for those with disabilities, older adults, and those with limited English proficiency

Hepatic Nrf2 expression is altered by quercetin supplementation in X-irradiated rats

P. 539-546Whole‑body irradiation has been associated with liver function alterations. Ionizing radiation exposure increases oxidative stress and antioxidants can activate transcription of antioxidant target genes. In the present study, modifications of the liver antioxidant system were evaluated at 7 and 30 days following sub‑lethal whole‑body X‑irradiation in male Wistar rats, which were intragastrically supplemented with quercetin or control solvent for 4 days prior to and 6 days following irradiation. Animal groups were as follows: CS, control, solvent‑supplemented; CQ, control, quercetin‑supplemented; RS, irradiated, solvent‑supplemented; and RQ, irradiated, quercetin‑supplemented. After 7 days, liver tissue from RS animals demonstrated marked hydropic panlobular degeneration with Mallory bodies in ballooning hepatocytes. These changes were mostly reversed in RQ rats. Lipid peroxidation in addition to copper/zinc superoxide dismutase (Cu/Zn‑SOD), nuclear factor (erythroid‑derived 2)‑like 2 (Nrf2) and Kelch‑like ECH‑associated protein 1 (Keap1) protein expression levels were all increased by X‑irradiation, but significantly decreased by quercetin supplementation. Catalase (CAT) and NAD(P)H: quinone oxidoreductase 1 (NQO1) expression levels remained high in irradiated rats regardless of quercetin supplementation. After 30 days, the liver from RS animals had small portal infiltrates and diffuse cytoplasmic vacuolization, with reduced lipid peroxidation and reduced expression levels of CAT, NQO1, Nrf2 and Keap1, but consistently elevated Cu/Zn‑SOD expression. RQ animals indicated reduced expression levels of Nrf2 and Keap1 30 days after irradiation. The present study demonstrated a quercetin‑induced reduction of the oxidative stress‑associated increase in Nrf2 expression that may be useful for preventing cancer cell survival in response to ionizing radiation exposure.S

Phase 2 Outreach Plan: Georgia DOT ITS4US Deployment Project- Safe Trips in a Connected Transportation Network

693JJ32250011The Georgia Department of Transportation ITS4US Deployment project, Safe Trips in a Connected Transportation Network (ST-CTN), is leveraging innovative solutions, existing deployments, and collaboration to make a positive impact using transportation technology to support safety, mobility, sustainability, and accessibility. The ST-CTN concept is comprised of an integrated set of advanced transportation technology solutions (connected vehicle, transit signal priority, machine learning, predictive analytics) to support safe and complete trips, with a focus on accessibility for those with disabilities, older adults, and those with limited English proficiency. This document serves as the Outreach Plan for the deployment project. The Outreach Plan consists of the public relations and media strategy for communicating information about the project. It also defines the Outreach Site Lead for coordinating requests and the Site Outreach Spokesperson who will speak for the project. The Outreach activities described in this plan will be consistent with the Complete Trip Integration Plan being prepared for this project

Hypoxia and oxidative stress in breast cancer: Tumour hypoxia – therapeutic considerations

Conclusive research has shown that regions of acute/chronic hypoxia, which exist within the majority of solid tumours, have a profound influence on the therapeutic outcome of cancer chemotherapy and radiotherapy and are a strong prognostic factor of disease progression and survival. A strong argument therefore exists for assessing the hypoxic fraction of tumours, prior to patient treatment, and to tailor this treatment accordingly. Tumour hypoxia also provides a powerful physiological stimulus that can be exploited as a tumour-specific condition, allowing for the rationale design of hypoxia-activated anticancer drugs or novel hypoxia-regulated gene therapy strategies

Normal tissue toxicity after small field hypofractionated stereotactic body radiation

Stereotactic body radiation (SBRT) is an emerging tool in radiation oncology in which the targeting accuracy is improved via the detection and processing of a three-dimensional coordinate system that is aligned to the target. With improved targeting accuracy, SBRT allows for the minimization of normal tissue volume exposed to high radiation dose as well as the escalation of fractional dose delivery. The goal of SBRT is to minimize toxicity while maximizing tumor control. This review will discuss the basic principles of SBRT, the radiobiology of hypofractionated radiation and the outcome from published clinical trials of SBRT, with a focus on late toxicity after SBRT. While clinical data has shown SBRT to be safe in most circumstances, more data is needed to refine the ideal dose-volume metrics